Scorpion β-toxin interference with Na <inf>v</inf> channel voltage sensor gives rise to excitatory and depressant modes

Abstract:

Scorpion β toxins, peptides of ~70 residues, specifically target voltage-gated sodium (Na V) channels to cause usedependent subthreshold channel openings via a voltage-sensor trapping mechanism. This excitatory action is often overlaid by a not yet understood depressant mode in which Na V channel activity is inhibited. Here, we analyzed these two modes of gating modification by β-toxin Tz1 from Tityus zulianus on heterologously expressed Na V1.4 and Na V1.5 channels using the whole cell patch-clamp method. Tz1 facilitated the opening of Na V1.4 in a use-dependent manner and inhibited channel opening with a reversed use dependence. In contrast, the opening of Na V1.5 was exclusively inhibited without noticeable use dependence. Using chimeras of Na V1.4 and Na V1.5 channels, we demonstrated that gating modification by Tz1 depends on the specific structure of the voltage sensor in domain 2. Although residue G658 in Na V1.4 promotes the use-dependent transitions between Tz1 modification phenotypes, the equivalent residue in Na V1.5, N803, abolishes them. Gating charge neutralizations in the Na V1.4 domain 2 voltage sensor identified arginine residues at positions 663 and 669 as crucial for the outward and inward movement of this sensor, respectively. Our data support a model in which Tz1 can stabilize two conformations of the domain 2 voltage sensor: a preactivated outward position leading to Na V channels that open at subthreshold potentials, and a deactivated inward position preventing channels from opening. The results are best explained by a two-state voltage-sensor trapping model in that bound scorpion β toxin slows the activation as well as the deactivation kinetics of the voltage sensor in domain 2. © 2012 Leipold et al.

Año de publicación:

2012

Keywords:

Fuente:

scopus